Can interoceptive sensitivity provide information on the difference in the perceptual mechanisms of recurrent and chronic pain? Part I. A retrospective clinical study related to multidimensional pain assessment.

OBJECTIVES: Although neurobiological research has shown that interoception plays a role in the perception of pain and its chronification, the relationship between interoceptive sensitivity and pain has not been definitively confirmed by clinical studies. The aim of this study was therefore to better understand the relationship between interoceptive sensitivity, somatization, and clinical pain, and to identify any differences in the interoceptive sensitivity of patients with recurrent vs. chronic pain. METHODS: Scores from 43 Chronic pain subjects, assessed using ICD-11 Criteria; 42 healthy subjects (without pain or psychiatric disorders); and 38 recurrent pain subjects on the Multidimensional Assessment of Interoceptive Awareness (MAIA), Body Perception Questionnaire (BPQ-SF), Somatosensory amplification scale (SSAS), Patient Health Questionnaire (PHQ-15), Symptom Checklist-Revised (SCL-90-R), and Italian Pain Questionnaire (IPQ) were compared. RESULTS: Negative attention to the body was indicated by higher scores of psychosomatic dimensions as SSAS, SCL90R somatization, and PHQ-15 in recurrent, but especially chronic pain (p<0.000 for all). An increase in psychosomatic dimension scores (i.e., somatization, somatosensory amplification) was associated with an increase in both autonomic nervous system reactivity (ANSR) dimension scores and the negative influence of the Not-worrying, attention regulation and trusting of the MAIA. In contrast, the presence of pain and scores for its dimensions with associated with lower supra-diaphragmatic activity as per the BPQ. CONCLUSIONS: Pain chronification might depend on both the impairment of interoceptive sensitivity and an increase on psychosomatic dimensions via modification of ANSR hyperactivity and a reduction of the MAIA Not-worrying dimension.

Defensive responses in invertebrates: Evolutionary and neural aspects.

Lower invertebrates exhibit both morphological and behavioral defensive responses to aversive stimuli, characterized by withdrawal. Typical immobility responses are "sinking" in Rotifers and "crumpling" in Cnidaria. They also display individual adaptation and phenotypic plasticity but not tonic immobility (TI). The higher phyla with a more organized nervous system have developed morphological and behavioral defensive strategies including TI, occurring both in natural and laboratory conditions. There are general but also specific prey-predator mechanisms, that have coevolved leading to reciprocal phenotypic plasticity. The evolution of traits differentiated in subpopulations has been described in many species (animal personality). In insects the variability in TI is heritable and inversely related to boldness. In two genetic lines of beetles with long and short TI duration, the long duration line has higher survival rate but lower mating success (behavioral syndromes). TI may have an adaptive significance also in intraspecific interactions in the context of sexual selection.

Environmental, ecological and methodological factors of Tonic Immobility (TI) modulation.

Modulation of Tonic Immobility (TI) concerns environmental and individual factors. TI is modulated by processes of habituation and sensitization. In poikilotherm frog and lizard, TI duration is much shorter at usual environmental temperatures and is potentiated at higher or lower temperatures, as the last resource for survival. During ontogeny, age may differentially affect TI susceptibility to the induction procedures, as in the case of newborn ectothermic and older endothermic rabbits. TI duration displays a daily rhythm, with longer TI in the night. Its resistance to habituation indicates that in the dark TI is the most prominent defense against nocturnal predators. In all studied species, there is synchronization of the prey's defensive responses with the feeding activity of predators. Ecological factors and exposure to different anthropogenic environmental pressures may alter morphology, behavior and TI in wild populations. TI duration has been associated with a genomic region comprising the dystrophin gene on quail chromosome 1.

The neuroethological approach to defense in rabbit.

In this chapter we review the neuroethological approach correlating behavior and dorsal hippocampal activity recorded in rabbits in laboratory conditions or in a semi-natural enclosure and exposed to intra and interspecific confrontations. Behaviors of the same modality, i.e., immobility, and the same motivation, i.e., defense, can be distinguished by a different pattern of hippocampal activity, in terms of the relative ratio of RSA (rhythmic slow activity), and LIA (large amplitude irregular activity), and of RSA frequencies. In addition, the frequency and the duration of RSA episodes represent critical indicators of the amount of awareness during immobility conditions. The neural pattern is also differentially affected by dynamic (a live cat) and static (a stuffed sparrow hawk) stimuli. On a neuroethological basis, the hippocampal profile of TI, characterized by the prevalence of LIA, is similar to a sparrow-hawk exposure and to the submissive posture in a conspecific confrontation.

Neurophysiological mechanisms involved in tonic immobility (TI).

This chapter summarizes the main neurophysiological characteristics of tonic immobility (TI), in many susceptible species of mammals and birds. During TI, cortical EEG shows high voltage slow waves whose amount is affected by events preceding TI induction and is positively correlated with TI duration. The pattern of hippocampal activity helps to predict TI onset and TI termination. Both polysynaptic flexor and monosynaptic heteronymous reflexes are depressed independently from the EEG activity. Brain metabolism, signaled by glycogen mobilization and glucose utilization, indicates a reduced neuronal activity during TI. Learned avoidance responses to shock can be extinguished during TI and recover after TI. Moreover, during TI animals may learn how to avoid the shock by a motor response that may be followed by TI interruption. Decortication, decerebellation and telencephalic sections do not affect TI characteristics, whereas ponto-mesencephalic sections abolish both righting reflexes and TI.

Neuromediators and defensive responses including tonic immobility (TI): Brain areas and circuits involved.

Serotonin, acetylcholine and GABA are the neuromediators most involved in tonic immobility (TI). TI duration, in fact, decreases in rabbits following systemic serotonin administration and in guinea pigs following serotonin microinjection administration into the amygdala owing to the activation of fear-related GABAergic inhibitory mechanisms. On the other hand, repeated TI inductions in rabbits and guinea pigs reduce brain serotonin turnover in several brain areas. Microinjections of the acetylcholine agonist carbachol into amygdala, hypothalamus and PAG increase TI duration and reduces other defensive responses to threatening stimuli in several animal species. The cholinergic and serotonergic systems exert different effects on TI in different regions of the PAG according to the receptors stimulated. Their combined action activates opioid-GABAergic neurons ultimately affecting TI duration. Mammals TI and human cataplexy are innate responses induced by different stimuli, although both characterized by deficiency in orexin, reduced muscle tone, normal jerk reflexes and preserved consciousness.

Neuroendocrine correlates of stress and tonic immobility.

Threatening stimuli challenging animal homeostasis are the primary events triggering defensive responses, including TI. The stress-response system (allostasis) is signaled by increased corticosteroid basal levels. In bird animal lines genetically selected for stress-induced corticosterone, there is a covariation between stress physiology and coping styles. Rabbit studies, in which the effects of TI are dissociated from those of induction per se, support the view that TI takes part in the homeostatic stress-response system. An increase of corticosterone is recorded just after the end of the induction procedure but not in the corresponding groups in which induction is followed by TI, suggesting a recovery process during TI. Similarly to corticosterone but in opposite direction, testosterone plasma levels decrease following induction and recover during TI. Recovery mechanisms are also suggested in two bird genotypes selected for long and short TI duration. The positive relation between corticosterone levels and TI duration has been confirmed after exogenous corticosterone administration.

Autonomic correlates of defense responses, including tonic immobility (TI).

Animal models of autonomic correlates of defense behavior range from fish to mammals. There is however no study reporting heart and respiratory rate, blood pressure and body temperature simultaneously recorded in the same animal in association to different forms of immobility in response to threat: freezing, restraint-sustained immobility and tonic immobility (TI). In a prey/ predator context freezing behavior is associated with bradycardia and no change in blood pressure but in other conditions (e.g., extreme stressful stimuli) may be associated with tachycardia and hypertension. Restraint-sustained immobility does not affect blood pressure but may reduce heart rate according to the type of stimulus and mechanical pressure. Blood pressure and heart rate oscillate during TI induction and adjust at basal levels during TI, sometimes gradually decreasing below basal levels. In conclusion, in all these passive defense responses, the immobility is not due to a blood pressure collapse.

Pain control in tonic immobility (TI) and other immobility models.

This chapter deals with the mechanisms modulating pain during TI and other immobility responses in different animal species. In mammals the presence of high voltage slow waves in the electroencephalogram during TI suggests the activation of the thalamic gate, a mechanism blocking all sensory information, including pain. In rabbits TI transiently suppresses all the behavioral responses to persistent nociceptive stimulation by the activation of an opioid mechanism outlasting TI offset by 1h. On the other hand, in rodents, also not injuring nociceptive stimuli applied during TI elicit a delayed opioid analgesia that develops within 45min. Moreover, both opioid and non-opioid mechanisms of analgesia have been observed. TI strongly reduces inflammatory responses by activating the vagal-neocortical-sympathetic axis, a feedback control of neuro-immune mechanisms. Several models of noxious and non-noxious restraint and of post-restraint immobility resembling TI have been proposed. Moreover in lizards, hyperalgesia occurs during and after TI.

Tonic immobility as a survival, adaptive response and as a recovery mechanism.

In this conclusive chapter, we review findings giving support to the hypothesis that TI represents an adaptive, survival response to threatening situations. In models of prey-predator interactions, in vertebrates and invertebrates, there are evidence that immobility per se contributes to survival, as the predator loses interest for a prey in which TI is experimentally induced. TI duration is also reciprocally modulated by the evaluation of the risk factors in the environment, and by the opportunity to reach a safe refuge. This supports the adaptive value of TI and suggests that, during TI, the animal may be transiently aware of the environmental situation. As for the adaptive value of TI, genetic correlations with other behavioral systems contributing to fitness (e.g., mating) are taken into account. Moreover, neurophysiological and endocrine findings in mammals support our hypothesis that TI activates the mechanisms responsible for recovery from disruptive experiences and body lesions.

Synthesis of defense response characteristics.

In previous chapters, the available theories and experimental findings related to animals' defense responses have been reported and discussed in detail. This chapter reports their comprehensive synthesis, considering the main immobility-related responses in defense. Within the same modality (i.e., immobility) different kinds of immobility may in fact correspond to different functions and motivations, as proved by their neurobiological correlates profile.

Introduction to defensive behavior in vertebrates.

In this introductory chapter we describe the ethological basis of defensive behavior, including tonic immobility (TI). The defensive repertoire activated in response to threatening stimuli, both in natural and experimental conditions, consists of a system of interrelated behaviors influenced by two main dimensions, as distance from the threat and escapable/inescapable context. When the active strategy of escape is not feasible, passive immobility forms are adopted, the latter representing substitutes of actual escape. In an inescapable context, and at very short distance or in contact with the threatening stimulus, TI is adopted, or submissive posture in a social context. Physical restraint represents the strongest stimulus for TI induction. As a result of behavioral flexibility, subsets of animals within a population show a different capacity and modality to cope with aversive stimuli (animal personality). TI can be regarded as a trait of behavioral syndromes in species as mammals and avians.

Neural circuits of fear and defensive behavior.

Innate fear-related behavioral responses have evolved as strategies for survival. The neural circuits responsible for defensive responses, studied mainly in rodents, have been substantially preserved across evolution. Amygdala collects sensory information (visual, auditory and olfactory) in the cortical division and conveys it to the striatal output division. Distinct amygdala nuclei/subnuclei are activated by different fearful stimuli, such as exposure to a predator or to an aggressive conspecific. The same stimuli segregation is observed in downstream structures, i.e., hypothalamus and PAG. In guinea pigs, the circuits underlying Tonic Immobility (TI) and freezing in response to a natural predator, have been mapped in different subnuclei of the same amygdala area. In the PAG circuits, defensive responses are differentially represented along the dorso-ventral and rostro-caudal axis. The coordination of behavioral, anti-nociceptive and autonomic responses is due to the overlapping of the involved neurons in longitudinal columns.

The fear hypothesis and tonic immobility (TI) modulation: Early studies in chickens.

The hypothesis that fear is involved in the mechanisms of tonic immobility (TI) has been supported by early studies conducted in newborn and adult chickens. The susceptibility to TI changes during development in parallel to other fear responses. TI duration increases following exposure before induction to threatening stimuli such as electric shock, loud sound, stuffed sparrow hawk, as well as in unfamiliar conditions applied before and/or during testing. TI duration and susceptibility are increased by prey/predator eye contact and inversely related with the predator distance. TI duration increases following exposure before induction to threatening stimuli such as electric shock, loud sound, stuffed sparrow hawk, as well as in unfamiliar conditions applied before and/or during testing. The fact that the experimenter presence or the experimenter eye visibility represent a potential source of fear like a natural predator in chicks and in adult hens is controversial. The likely explanations for the contradictory results are discussed in the text. The rearing conditions, for instance, seem to be critical: repeated handling in the first days after hatching reduces the fear of human beings, decreasing TI duration in adulthood with a parallel increase in proximity scores to the experimenter. In chicks, exposure to withdrawal from a positive imprinting stimulus increases and decreases TI duration, respectively.

The formalin test does not probe inflammatory pain but excitotoxicity in rodent skin.

The most widely used formalin test to screen antinociceptive drug candidates is still apostrophized as targeting inflammatory pain, in spite of strong opposing evidence published. In our rat skin-nerve preparation ex vivo, recording from all classes of sensory single-fibers (n = 32), 30 units were transiently excited by formaldehyde concentrations 1-100 mM applied to receptive fields (RFs) for 3 min, C and Aδ-fibers being more sensitive (1-30 mM) than Aß-fibers. From 30 mM on, ~1% of the concentration usually injected in vivo, all RFs were defunctionalized and conduction in an isolated sciatic nerve preparation was irreversibly blocked. Thus, formaldehyde, generated a state of 'anesthesia dolorosa' in the RFs in so far as after a quiescent interphase all fibers with unmyelinated terminals developed a second phase of vigorous discharge activity which correlated well in time course and magnitude with published pain-related behaviors. Sural nerve filament recordings in vivo confirmed that higher formalin concentrations (> 42 mM) have to be injected to the skin to induce this second phase of discharge. Patch-clamp and calcium-imaging confirmed TRPA1 as the primary transducer of formaldehyde (10 mM) effects on mouse sensory neurons. However, stimulated CGRP release from isolated skin of TRPA1+/+ and TRPA1-/- mice showed a convergence of the saturating concentration-response curves at 100 mM formaldehyde, which did not occur with nerve and trachea preparations. Finally, skin-nerve recordings from C and Aδ-fibers of TRPA1-/- mice revealed a massive reduction in formaldehyde (30 mM)-evoked discharge. However, the remaining activity was still biphasic, thus confirming additional unspecific excitotoxic actions of the fixative that diffuses along still excitable axons as previously published. The multiplicity of formaldehyde's actions requires extensive discussion and literature review, leading to a fundamental reevaluation of the formalin test.

A retrospective observational study comparing somatosensory amplification in fibromyalgia, chronic pain, psychiatric disorders and healthy subjects.

OBJECTIVES: Somatosensory amplification (SA) has been described as an important feature of somatoform disorders, and an "amplifying somatic style" has been reported as a negative connotation of body perception. As widespread pain (WSP) in fibromyalgia (FM) is due to a central sensitization (CS) rather than organic alterations, there has been discussion as to whether FM is equivalent to or distinct from somatization disorder (SD). Assuming SD and FM are two distinct entities, an increase in somatic amplification should be expected only in subjects who have SD, regardless of the type of pain they experience. Purpose of the study was to explore the magnitude of SA in FM, and whether this depends on the association with SD. METHODS: FM (n=159) other forms of chronic pain (OCP, n=582), psychiatric (Psy, n=53) and healthy (H, n=55) subjects were investigated using the Somatosensory Amplification Scale (SSAS), Illness Behavior Questionnaire, (IBQ), Italian Pain Questionnaire (IPQ), and Cold Pressor Test (CPT) in a retrospective observational study. RESULTS: FM subjects displayed higher SSAS scores than the other groups. High SSAS score was associated with FM (OR=8.39; 95%CI: 5.43-12.46) but not OCP. Although FM has the highest prevalence of SD (x2=14.07; p=.007), high SSAS scores were associated with SD in OCP but not in FM. CONCLUSIONS: Unlike in OCP, in FM high SSAS scores were independent of the presence of SD. From a biopsychosocial perspective, SSAS may be a factor associated with the onset of FM.

An evolutionary approach to hypnotizability.

We propose here an evolutionary interpretation of the presence of highly hypnotizable persons (highs) among the general population. Current experimental evidence suggests the presence of stronger functional equivalence between imagery and perception, non-opioid cognitive control of pain, favorable cardiovascular asset, and greater interoceptive sensitivity in highs. We hypothesize that these characteristics were greatly relevant to our ancestors' survival, and that they may have facilitated the natural selection of individuals who are now named "highs" due to one of their side effects - the proneness to accept suggestions - as part of the reported physiological features. Unfortunately, our theoretical hypothesis cannot be currently experimentally proven. We believe, however, that looking at hypnotizability in a naturalistic, evolutionary perspective may emphasize the importance of its physiological correlates in daily life and in the prediction of the outcome of medical treatments.